rs886041715

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate

The NM_020988.3(GNAO1):c.118G>A(p.Gly40Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 15/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GNAO1
NM_020988.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.59

Variant links:

Genes affected

GNAO1 (HGNC:4389): (G protein subunit alpha o1) The protein encoded by this gene represents the alpha subunit of the Go heterotrimeric G-protein signal-transducing complex. Defects in this gene are a cause of early-onset epileptic encephalopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

GNAO1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a region_of_interest G1 motif (size 13) in uniprot entity GNAO_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_020988.3

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the GNAO1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 70 curated pathogenic missense variants (we use a threshold of 10). The gene has 43 curated benign missense variants. Gene score misZ: 3.1919 (above the threshold of 3.09). Trascript score misZ: 4.549 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy, 17, neurodevelopmental disorder with involuntary movements, developmental and epileptic encephalopathy, movement disorder.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 16-56192353-G-A is Pathogenic according to our data. Variant chr16-56192353-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 666297.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAO1	NM_020988.3 link	c.118G>A	p.Gly40Arg	missense_variant, splice_region_variant	Exon 1 of 9	ENST00000262493.12	NP_066268.1	P09471-1Q8N6I9B3KP89
GNAO1	NM_138736.3 link	c.118G>A	p.Gly40Arg	missense_variant, splice_region_variant	Exon 1 of 8		NP_620073.2	P09471-2Q8N6I9B3KP89Q6AWC5
GNAO1	XR_007064866.1 link	n.865G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 9
GNAO1	XM_011523003.4 link	c.-601G>A		upstream_gene_variant			XP_011521305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAO1	ENST00000262493.12 link	c.118G>A	p.Gly40Arg	missense_variant, splice_region_variant	Exon 1 of 9	1	NM_020988.3	ENSP00000262493.6		P09471-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.16e-7

AC:

AN:

1396334

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

698062

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.49e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 17

Pathogenic:1

Jan 01, 2015

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;.;D;.;D;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

.;D;D;D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

4.5

H;.;H;H;.;.

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-6.4

D;.;.;D;.;.

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;.;.;D;.;.

Sift4G

Pathogenic

0.0

D;.;.;D;D;.

Polyphen

1.0

D;.;D;D;.;.

Vest4

0.95

MutPred

0.90

Gain of MoRF binding (P = 0.0073);Gain of MoRF binding (P = 0.0073);Gain of MoRF binding (P = 0.0073);Gain of MoRF binding (P = 0.0073);Gain of MoRF binding (P = 0.0073);Gain of MoRF binding (P = 0.0073);

MVP

0.99

MPC

2.9

ClinPred

1.0

GERP RS

4.8

Varity_R

0.97

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over